JPS62103018A - Production of nicorandil preparation - Google Patents

Abstract

PURPOSE:Nicorandil, as a remedy for stenocardia, is combined with an organic acid selected from fumaric, oxalic, salicylic acids and pharmaceutically prepared to give a nicorandil preparation with improved stability to moisture. CONSTITUTION:Nicorandil, N-(2-hydroxyethyl)nicotinamide nitrate ester is mixed with at least one of organic acids selected from fumaric, oxalic, salicylic, tartaric and glutaric acids and made into a desired preparation such as tablets, capsules or suppository. The resultant preparations have improved stability, especially a great stride of improved stability to moisture. The amount of the organic acid is over 0.1wt%.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) The present invention relates to a method for producing a stable preparation of nicorandil, which is very useful as a medicine. That is, the present invention provides nicorandil [chemical name: N-(2-h droxyethyl) nicotinic acid amide nitrate] with one or more selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid, and glutaric acid. This is a method for producing a stable nicorandil preparation, which is characterized in that it is prepared by mixing an organic acid.

Nicorandil is an effective drug for the treatment of various types of angina pectoris with little effect on cardiac hemodynamics and cardiac function. Kosho 5
8-17483, Japanese Unexamined Patent Publication No. 53-9323).

Q (', j)However, although nicorandil preparations are relatively stable in dry conditions, they are unstable, especially when exposed to humidity, and special consideration must be given to 1n degrees when manufacturing and storing the preparations. However, it requires a large amount of cost, such as completely moisture-proof packaging.

The inventors of the present invention have conducted extensive research into methods for manufacturing formulations that are stable against humidity, and have found that the stability of nicorandil formulations is improved by mixing certain types of organic acid crystals or crystalline powders into formulations. It has been found that the stability against humidity is dramatically improved.

Furthermore, as organic acids effective for stabilizing nicorandil preparations, dibasic acids such as fumaric acid, oxalic acid, glutaric acid, tartaric acid, and salicylic acid have been found to exhibit particularly excellent stabilization, and the present invention has been completed. It's arrived.

. Zhan Yu's nicorandil crystals or crystalline powder, excipients, and disintegrants.

Lubricants 9 For compositions containing pharmaceutical carriers such as colorants, binders, ointment bases, and tape bases, the above-mentioned fumaric acid,
Ill or two or more organic acids selected from the group of oxalic acid, salicylic acid, tartaric acid, and glutaric acid are blended into the desired form, ie, tablets and capsules, by a conventional method.

Solid preparations such as granules and suppositories, and transdermal preparations such as ointments and tapes can be used. In the case of solid preparations, the above-mentioned pharmaceutical carriers include, for example, lactose, corn starch, mannitol, kaolin, calcium carboxymethylcellulose, talc, calcium carbonate, and calcium stearate.

Magnesium stearate and the like are used.

For transdermal agents, polyvinyl alkyl ether.

Poly(meth)acrylate, polyurethane, polyester.

Polyamide, ethylene-vinyl acetate copolymer, acrylic acid alkyl ester-acrylic acid copolymer, etc. are used, and tackifiers, softeners, etc. are added as necessary.

The amount of organic acid required to stabilize a nicorandil formulation varies depending on the manufacturing method, but the amount of organic acid added to the formulation is 0.
The purpose can be achieved by adding 1% by weight or more.

Production-■ The preparation obtained according to the present invention has excellent stability. The present invention will be described below with reference to Examples, but the present invention is not limited thereto.

myu tablet prescription (in 1 tablet) nicorandil 10 (mg) lactose
76.5 corn starch
10 fumaric acid 3 stearic acid.

Total 100100 ( Nicorandil crystals 200g, lactose 1530g.

Put 200 g of corn starch and 80 g of fumaric acid pulverized powder (average particle size about 3 μm) into a product mixer,
After mixing for 0 minutes, add 10 g of magnesium stearate and mix for 1 minute.

The above mixed powder was pressed into a single tablet machine equipped with a 7 mm diameter mortar and a flat mold to give a total of 100 mg per tablet at a total pressure of approximately 1.
Compression molded in tons.

For comparison, tablets were manufactured under the same conditions in which fumaric acid in the formulation of the example was replaced with the same amount of lactose.

Put both tablets into glass bottles and seal them with 413 bottles.
℃ - 40℃ for 3 months and in open condition - relative humidity 61.5
%-3 months respectively, and the stability was compared. The survival rate is shown in Table 1, taking the value before acceleration as 100%.

Table 1 Capsules (in 1 capsule) Nicorandil 10 (mg) Mannitol 44 Carboxymethyl cellulose calcium 5 Salicylic acid 40 Stear 1 Calcium total 100,100 (nicorandil crystals 200 g, mannitol 880 g, carboxymethyl cellulose calcium 100 g, salicylic acid crystals 800 g and calcium stearate 20 g) After uniformly mixing in a plastic bag, the mixture is treated with a roller fan bacter and sieved through a 10-mesh sieve to form slug granules.

100 mg of the above Surasog granules were filled into No. 3 capsules.

For comparison, capsules were produced under the same conditions in which the same amount of mannitol was substituted for the salicylic acid in the formulation of the example.

Both capsules were placed in a glass bottle, and a desiccant (silica gel) was added and the bottle was sealed at 40°C for 3 months, and a desiccant was not added and the bottle was sealed at 40°C for 3 months, respectively, and the stability was compared. did.

The residual rate is shown in Table 2, taking the value before acceleration as 100%.

Table 2 m Granules (1000mg) Nicorandil 50 (mg) Mannitol 920 Oxalic acid 10 Corn starch total 1000mg Nicorandil crystals 100g, Mannitol 1゜840g
and 20 g of oxalic acid were placed in a mixer and mixed for 20 minutes, then 400 g of 10% corn starch paste was added and kneaded for 10 minutes.

The mixture was granulated using a cylindrical granulator equipped with a 1.0 mm diameter net. The granules were dried in a wall dryer at 50°C for 4 hours. After drying, the particles were sieved using a sieve of 10 pieces/yu.

For comparison, granules were produced under the same conditions in which the same amount of mannitol was substituted for the oxalic acid in the formulation of the example.

Put the granules in the same order into glass bottles and keep them tightly closed for 40 minutes.
°C - 40 °C for 3 months and in the open - relative humidity 61.
Acceleration was performed for 5%-3 months, and the stability was compared.

The survival rate is shown in Table 3, taking the value before acceleration as 100%.

Table 3 Ointment (1000mg) Nicorandil 20mg fumaric acid
20mg plastibase
T total: 1000 mg 2 g of nicorandil crystals, 2 g of fumaric acid, and a small amount of Plastibase were placed in an Ishikawa vacuum stirring shaker and kneaded for 10 minutes. Furthermore, add and knead Plastibase little by little until the total f.
Add up to filoog and mix evenly.

For comparison, an ointment was produced under the same conditions in which the fumaric acid in the formulation of the example was replaced with the same amount of Plastibase.

Both ointments were placed in plastic ointment containers, sealed at 40°C for 2 months, and at 60°C for 1 week, with and without a desiccant (/storage gel), respectively, to accelerate the aging process and compare the stability. The survival rate is 4th when the survival rate is taken as 100% before acceleration.
As shown in the table.

Table 4 Tape preparation Nicorandil
5 parts salicylic acid
5 parts Octyl acrylate-acrylic acid copolymer 100 parts Ethyl acetate
After dissolving 5 parts of nicorandil and 5 parts of salicylic acid in 400 parts of an ethyl acetate solution of 300 parts of 25% inoctyl acrylate (95% by weight)-acrylic acid (5% by weight) copolymer, this was dissolved in a thickness of 80 parts. A tape preparation is obtained by coating and drying the mixture onto the surface of a polyethylene film having a thickness of 50 μm so that the thickness after drying becomes 50 μm.

For comparison, instead of salicylic acid in the example formulation,
A tape preparation was produced under the same conditions in which the same amount was replaced with an isooctyl acrylate (95% by weight)-acrylic acid (5% by weight) copolymer solution.

As shown in the Examples in Table 5 and above, the nicorandil formulation of the present invention is extremely stable, and in particular, the stability against humidity is dramatically improved.

Claims (1)

[Claims] A method for producing a stable nicorandil preparation, which comprises mixing nicorandil with one or more organic acids selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid, and glutaric acid.